Some of the information set forth herein has been published (see Masao Koyama, T. Ross Kelly and Kyoichi A. Watanabe, Novel Type of Potential Anticancer Agents Derived from Chrysophanol and Emodin. Some Structure-Activity Relationship Studies, [Part 1] Journal of Medicinal Chemistry, 31:283-284 (1988) which was distributed by the publisher on Jan. 29, 1988; and Masao Koyama, Kiyobumi Takahashi, Ting-Chao Chou, Zbigniew Darzynkiewicz, Jan Kapuscinski, T. Ross Kelly, and Kyoichi A. Watanabe, Intercalating Agents with Covalent Bond Forming Capability. A Novel Type of Potential Anticancer Agents. [Part 2] Derivatives of Chrysophanol and Emodin, Journal of Medicinal Chemistry, 32:1594 (1989)).
A number of analogues of certain antitumor intercalating agents, such as ellipticine (Le Pecq, J.-B., et al., Proc. Natl. Acad. Sci. U.S.A. 71:5078 (1974); Guthrie, R. W., et al., J. Med. Chem 18:755 (1975)) 4'-(9-acridinylamino) methanesulfon-m-aniside (m-AMSA, amsacrine), (Denny, W. A., et al., J. Med. Chem. 25:276 (1982)) and anthracycline antibiotics (e.g., doxorubicin) (Mosher, C. W., et al., J. Med. Chem. 25:18 (1982); Seshadri, R., et al., J. Med. Chem. 26:11 (1983); Myers, C. Cancer Chemother. 8:52 (1986)) have been synthesized in order to gain better therapeutic potential. However, preliminary screening data show that there is no straightforward structure-activity relationship within each group. These results seem to suggest that although intercalation may be a necessary condition, it may not be sufficient and other factors may be involved that per se potentiate the anticancer activity.
Studies on the mechanism of anticancer action of antibiotic CC1065 (Chidester, C. G., et al., J. Am. Chem. Soc., 103: 7629 (1981); Kanatomo, S., et al., Chem. Pharm. Bull., 29:229 (1981), Li, L. H. et al., Cancer Res. 42:999 (1982)) show that it binds to the minor groove of DNA by nonintercalative means and then slowly alkylates the amino group of adenine by opening the cyclopropane ring in the antibiotic molecule. With CC1065, covalent binding of the drug with DNA, therefore, seems to be important for its potent cytotoxic activity. Mere physical interaction between the drug and DNA may not be sufficient.
These considerations point to the development of intercalators with slow alkylating capability. Such intercalators will bind covalently and hopefully should eventually disrupt the DNA function.
The compounds of the present invention have both intercalating and alkylating functionalities, and as such are potential anticancer agents.
The compounds of this invention may also be useful as biochemical probes for biological reactions essential for DNA synthesis. Recent studies indicate that m-AMSA inhibits the topoisomerization and catenation reactions of DNA topoisomerase II (Wang, J. C. Annu. Rev. Biochem, 54:665 (1985)), probably by trapping the enzyme-DNA complexes. (Nelson, E. M., et al., Proc. Natl. Acad. Sci. U.S.A. 81:1361 (1984)); Chen, G. L., et al., J. Biol. Chem. 259:13560 (1984)). Other substances, such as etoposide (VP-16), adriamycin, and ellipticine (Kuhn, K. W., et al., Natl. Cancer Inst. Monogr. 4:61 (1987)) also stabilize the cleavable complex between DNA topoisomerase II and DNA.
In the present invention, we show that the incorporation of an alkylating group into some DNA intercalating agents greatly enhances their antileukemic properties.